tbuckley/cabot-search huggingface dataset:
Response assessment and toxicity in patients treated with immune checkpoint inhibitors in solid tumors : A comprehensive cancer care center experience from India.
Authors: Prashant Mehta, Cheemala Sushmitha, Siddarth Sood, Shekhar Anand, Amit Badola, Anisha Raju, Raman Gupta
Journal: Journal of Clinical Oncology (2022)

e14562 Background: Checkpoint inhibitors are approved in various solid malignancies in either first-line or following progression on chemotherapy. These have shown good efficacy with low toxicity. However, there are very few studies from Indian centers. The purpose of the study was to assess the real world efficacy and toxicity in patients treated with Immunotherapy (IO) in various solid malignancies. Methods: The present study is a retrospective single-center hospital-based registry study that included 94 patients treated with immune checkpoint inhibitors in various solid malignancies from January 1, 2017 to December 31, 2020. The investigator assessed response at 3-months post-initiation of treatment has been reported. Patients who received less than two months of Immunotherapy were excluded in response analysis. Adverse events during IO were documented and graded using CTCAE (Common terminology criteria for adverse events), v.5.0. All statistical analysis was performed using Microsoft Excel 2016 and R software (Rx 64 version 3.6.2). Results: Sixty-nine patients who received more than 2 months of IO were assessed. Baseline characteristics of patients are listed in table 1. Lung cancer 29% (n= 27) Head and neck cancer 22% (n=21) and metastatic renal cell carcinoma 10% (n=9) were the common cancers where IO was given. Overall response rate at 3 months was 55% (n=38). Progressive disease and stable disease were seen in 39% (n=27) and 6% (n=5) patients respectively. The reported severe adverse events were pneumonitis, colitis, and hepatitis, with Grade 3 or more toxicities were in 7% (5/69) patients. Conclusions: IO was associated with clinical benefit and fewer toxic effects; however, increased treatment cost remains a significant concern in developing countries like India.[Table: see text]
A phase II, open-label, pilot study evaluating the safety and activity of liposomal irinotecan (Nal-IRI) in combination with 5-FU and oxaliplatin (NALIRIFOX) in preoperative treatment of pancreatic adenocarcinoma: NEO-Nal-IRI study.
Authors: Sherise C. Rogers, Brian Hemendra Ramnaraign, Kathryn Hitchcock, Steven J. Hughes, Ji-Hyun Lee, Anita Ahmed Turk, Karen Bullock Russell, Ibrahim Nassour, Ahmad El-Far, Jesus C. Fabregas, Ryan M. Thomas, Ilyas Sahin, Carmen Joseph Allegra, David L. DeRemer, Thomas J. George
Journal: Journal of Clinical Oncology (2022)

TPS4196 Background: Neoadjuvant treatment for potentially curable pancreatic cancer (PDAC) is increasing in acceptability, but a standard regimen has yet to be established. Multiple studies have demonstrated feasibility and effectiveness of the FOLFIRINOX (5-fluorouracil, leucovorin, oxaliplatin and irinotecan) regimen in the perioperative setting. However, FOLFIRINOX often requires dose modifications, delays and growth factor support due to excessive toxicity which can complicate care delivery when given pre-op. Liposomal irinotecan injection (Nal-IRI) is FDA approved in combination with 5-FU/LV with a well-tolerated safety profile in relapsed, refractory metastatic PDAC. The current study aims to substitute Nal-IRI for traditional irinotecan in the standard FOLFIRINOX regimen (NALIRIFOX) and to demonstrate safe and effective neoadjuvant delivery. Methods: This phase 2, open-label, multicenter single-arm study focuses on patients (pts) with operable PDAC without metastatic disease. Other key eligibility criteria include age ≥18 years, resectability confirmed by multiD GI tumor board (resectable vs. borderline), adequate cardiac, renal, hepatic function and ECOG performance status of 0 to 1. Pts receive NALIRIFOX regimen as per the table every 2 weeks for four months followed by disease reassessment. Pts who remain surgical candidates will undergo surgical resection within 4 to 8 weeks following last dose of therapy. The primary endpoint is to assess safety and feasibility of regimen in pre-op setting. Secondary endpoints include R0 resection rate, clinical, biochemical and radiological response rate and patient-reported quality of life during treatment as measured by the NCI validated FACT-G scale. Enrollment continues to a maximum of 28 evaluable pts to demonstrate a reduction in historical 30-day post-op complication rate. Clinical trial information: NCT03483038. [Table: see text]
Tumor agnostic efficacy and safety of erdafitinib in patients (pts) with advanced solid tumors with prespecified fibroblast growth factor receptor alterations (<i>FGFRalt</i>) in RAGNAR: Interim analysis (IA) results.
Authors: Yohann Loriot, Martin H. Schuler, Gopa Iyer, Olaf Witt, Toshihiko Doi, Shukui Qin, Josep Tabernero, David A. Reardon, Christophe Massard, Daniel Palmer, Iwona Lugowska, Jermaine Coward, Marcelo Corassa, Kim Stuyckens, Huimin Liao, Saltanat Najmi, Constance Hammond, Ademi E. Santiago-Walker, Hussein Sweiti, Shubham Pant
Journal: Journal of Clinical Oncology (2022)

3007 Background: Erdafitinib (erda) is an oral selective pan-FGFR tyrosine kinase inhibitor approved to treat locally advanced or metastatic urothelial carcinoma (UC) in adults with susceptible FGFR3/2alt who have progressed during or after ≥ 1 line of platinum containing chemotherapy . FGFRalt are observed across a wide range of malignancies and may function as oncogenic drivers independent of the underlying tumor type. RAGNAR (NCT04083976) is an ongoing phase 2 open label, single arm tumor agnostic trial investigating the efficacy and safety of erda in pretreated adult and pediatric pts with advanced solid tumors and FGFRalt. Here, we report results from a planned IA of RAGNAR. Methods: Pts aged ≥ 6 y with advanced or metastatic solid tumors of any histology (except UC) with predefined FGFR1-4alt (mutations/fusions based on local/central test) and documented disease progression on ≥ 1 prior line of systemic therapy (tx) and no alternative standard tx received oral erda until disease progression or intolerable toxicity. The primary end point is objective response rate (ORR) by independent review committee (IRC). Secondary end points include investigator assessed ORR, duration of response (DOR), disease control rate (DCR), clinical benefit rate (CBR), PFS, OS, and treatment emergent adverse events (TEAEs). Results: As of the IA data cutoff, 178 pts were treated (median age 56.5 y [range 12-79], median 2 prior systemic tx). Only 9.0% of pts responded to last line of tx prior to study entry. ORR by IRC was 29.2% (95% CI, 22.7-36.5). Investigator assessed ORR was 26.4% (95% CI, 20.1-33.5). Responses were observed in 14 distinct tumor types, including gliomas, thoracic, gastrointestinal, gynecological, and rare tumors (Table). ORR in pts with FGFR mutations vs fusions was comparable (26.8% vs 27.0%, respectively). Median DOR, PFS, and OS were 7.1 mo (95% CI, 5.5-9.3), 5.2 mo (95% CI, 4.0-5.6), and 10.9 mo (95% CI, 7.9-14.3), respectively; DCR was 75.3% and CBR was 48.9%. All pts experienced TEAEs, including 69.1% with grade ≥ 3. Treatment-related serious TEAEs occurred in 7.3% of pts. Conclusions: RAGNAR data show, for the first time, evidence of efficacy for erda in heavily pretreated pts with a variety of hard to treat advanced FGFR+ malignancies, including glioblastoma, pancreatic, and salivary gland cancers. Safety was consistent with the known erda safety profile. Clinical trial information: NCT04083976. [Table: see text]
Peripheral blood t cell responses to immunotherapy related adverse events in metastatic non-small cell lung cancer.
Authors: Suneetha Amara, Mahvish Muzaffar, Praveen Namireddy, Li V. Yang
Journal: Journal of Clinical Oncology (2022)

e21047 Background: There has been prospective and retrospective evidence for the onset of immunotherapy (IO) related adverse events (irAE) and efficacy of anti programmed death (PD1) and Programmed death Ligand 1(PD L1) antibodies. The incidence of irAE in these studies ranged anywhere from 30-44%. There have been attempts in the past to cluster irAEs into distinct subtypes by T cell profiling before and after immunotherapy. Identifying the trend of CD4/CD8 changes during irAE may aid in finding ways to mitigate the severe toxicities, so the benefits of immunotherapy can be extended to far more number of patients. Methods: We have collected blood samples from 20 patients of Non Small Cell Lung Cancer patients (NSCLC) before each cycle of immunotherapy with informed consent. We have measured the different inflammatory markers such as IL6, IL10 using ELISA and isolated cellular components such as CD4, CD8 T cells along with others using magnetic bead technique, from these samples in our research laboratory at East Carolina University. We have also collected clinical information including the adverse events with their (Common Terminology Criteria for Adverse events) CTCAE 5.0 grading, different cell counts and C- reactive Protein (CRP). Results: In the cohort of 20 patients, 9 experienced irAE, out of which 6 had grade 2, including thyroiditis, pneumonitis, dermatitis, cytokine release syndrome (CRS), 1 had grade 3 pneumonitis, 1 had grade 4 pneumonitis and 1 had grade 1 CRS. When we looked at the CD4/CD8 ratio before each cycle, the one prior to the incidence of the irAE had at least 30-40% drop in the ratio consistently although there were minor fluctuations in the ratio at other times in both directions. Conclusions: Although most irAEs can be treated and reversed with steroids and other immunosuppressive agents, prolonged immunosuppression can lead to reduced efficacy of IO and development of undue opportunistic infections . Experience with IO has shown that earlier initiation of immunosuppression shortens the required treatment. However, given the challenge in the subtility of the earlier presentation, therapies are frequently delayed. Hence, biomarker to identify the early manifestations is of critical importance for early intervention. Studies suggest there is clonal expansion of CD8 T cells preceding grade 2-3 irAEs. Studies also indicate that increased T cells in the tumor is indicative of response to immunotherapy. Our observation suggests that increased CD8 in proportion to CD4 in the peripheral blood precedes the onset of irAE. It is unclear as to how this leads to increased toxicity when the immunotherapy treatment works by affecting T cell function. One possible explanation is that the T cell response in the tumor tissue is beneficial, however, T cell response in the peripheral blood may indicate response against self antigens leading to toxicities in the form of irAE.
Preliminary data of a prospective study on the safety and efficacy of donafinib combined with anti-PD-1 antibody as adjuvant therapy for patients with hepatocellular carcinoma (HCC).
Authors: Xueli Bai, Yiwen Chen, Tingbo Liang
Journal: Journal of Clinical Oncology (2022)

e16131 Background: Surgical resection is one of the most effective treatments for HCC. However, the recurrence rate after hepatectomy is still very high with the 5-year recurrence rate of 60̃70%, which is even higher in patients with high-risk recurrence factors (the cumulative 1-year recurrence rate was about 50% without intervention). Here investigators intended to explore the safety and efficacy of donafenib combined with anti-PD-1 antibody as adjuvant therapy for HCC patients with high risks of recurrence. Methods: In this single-center study, eligible HCC patients with high-risk recurrence factors after radical surgery were recruited to receive donafenib combined with anti-PD-1 antibody for six months. The starting dose of donafenib was 100 mg PO BID in the first six patients and then reduced to 100 mg PO QD at the investigator’s discretion on tolerability in the adjuvant setting. For patients who started with donafenib 100 mg QD, the dose could be escalated to 100 mg BID from the second 21-day cycle if there were no experience grade ≥2 major adverse reactions (i.e. hand-foot syndrome, abnormal liver or kidney function, and blood cell decreased) reported in cycle 1. The primary endpoint was the cumulative 1-year recurrence-free survival rate. The secondary endpoints were recurrence-free survival (RFS), overall survival, quality of life (QoL) measured with FACT- Hepatobiliary questionnaire, and adverse events (AEs). Results: Between June 2020 and December 2021, thirteen patients with BCLC stage A-B HCC were enrolled. 11/13 (84.6%) patients had microvascular invasion (8 w/ M1 and 3 w/ M2). 11/13 (84.6%) patients had one tumor. 4/13 (30.8%) patients had tumor size ≥5 cm and 4/13 (30.8%) had satellite nodules. The median tumor size was 3.00 cm (IQR 2.60 to 6.00) and 3.29 cm (IQR 2.20 to 6.50) based on pathological findings and image, respectively. Eleven patients were included in efficacy analysis (two were excluded due to ineligibility). The median duration of follow-up was 8.30 months (IQR 2.90-14.40). Two patients experienced recurrence. The cumulative 1-year recurrence-free survival rate was 80% (90%CI, 49% to 93%). The median RFS was not reached. QoL showed a trend of improvement after 9 weeks of treatment. Among all the patients who received donafenib plus anti-PD-1 antibody, grade 3 treatment-related AEs (TRAEs) occurred in 7/13 (53.8%) patients (no grades 4 or 5 were reported). Common TRAEs included alanine aminotransferase increased (53.8%), aspartate aminotransferase increased (53.8%), blood bilirubin increased (38.5%), white blood cell decreased (38.5%), platelet count decreased (38.5%), rash (38.5%). No deaths were reported. Conclusions: The combination of donafinib and anti-PD-1 antibody as adjuvant therapy was well tolerated and demonstrated promising efficacy in HCC patients with high risks of recurrence. Clinical trial information: NCT04418401.
Identification of clinically actionable biomarkers via routine comprehensive genomic profiling across a large community health system.
Authors: Roshanthi K. Weerasinghe, Ryan Meng, Alexa K. Dowdell, Bela Bapat, Ann Vita, Brock Schroeder, Alisha Stein, Lauren Harold, Mark Schmidt, Shu-Ching Chang, Thomas Ward, Josiah Wagner, Stanley Piotrowski, Phillip G. Febbo, Carlo Bruno Bifulco, Brian Piening
Journal: Journal of Clinical Oncology (2022)

e15035 Background: Precision therapies and immunotherapies have revolutionized cancer care, with novel genomic biomarker-associated therapies being introduced into clinical practice rapidly. We assessed the utility of comprehensive genomic profiling (CGP)-based testing for identifying biomarkers associated with approved therapies, and therapies in precision medicine basket clinical trials (CT) across a large cohort of advanced cancer patients in the Providence health system. Methods: Advanced cancer patients were tested utilizing the Providence CGP workflow between 2019-2021. Clinical actionability was assessed for CGP and compared with results from an in silico 50-gene panel based on a previously utilized lab-developed test at Providence. Clinical actionability was assessed based on OncoKB and alterations were assigned as: FDA recognized (Level 1), standard of care (Level 2), FDA approved/investigational drug in another indication or having compelling clinical evidence (Level 3). CT matching was assessed based on enrollment criteria for ASCO-TAPUR, NCI-MATCH and My Pathway CTs at time of testing. Pooled electronic medical record and genomic data were curated and standardized. Results: Of the 3,218 advanced cancer patients tested with CGP, 52% were female, 80% were white, and median age was 67 years. Across 31 tumor types, the most commonly tested were lung (26%), bowel/colon (16%), and breast (9%). Overall, 48% of patients tested with CGP harbored at least one actionable biomarker (OncoKB Levels1/2/3). Clinical actionability was significantly higher in the CGP cohort compared to the in silico cohort based on presence of at least one Level 1 biomarker (45% vs. 19%, p &lt; 0.001). CGP cohort had higher proportion of patients with multiple/co-occurring Level 1 biomarkers compared to in silico cohort (20% vs. 9%, p &lt; 0.001). Of the most prevalent tumor types, 57% lung, 94% bowel/colon, and 37% breast had Level 1 alterations with CGP testing. Notably, 49% of CGP cohort vs. 23% in silico cohort (p &lt; 0.001) harbored a biomarker matching to one or more arms of the three basket CTs. Conclusions: CGP and small panel testing can both identify patients eligible for approved therapies and/or basket CTs with CGP having significantly higher clinical actionability and CT eligibility. We expect value of CGP to increase as biomarker actionability transforms clinical practice.
In vitro evidence that combination treatment with anti-PD-1 and anti-CD47 immunotherapy may not be efficient in human soft tissue sarcoma.
Authors: Zuzana Strizova, Andrej Ozaniak, Jitka Smetanova, Linda Capkova, Robin Bartolini, Robert Lischke, Jirina Bartunkova
Journal: Journal of Clinical Oncology (2022)

e23560 Background: Soft tissue sarcomas (STSs) are rare mesenchymal tumors. With more than 70 histological subtypes of STSs, studies defining robust biomarkers of therapeutic value are lacking. Even with the improvements in local control rates, metastases and death occur in 50% of patients that are diagnosed with high-risk STSs. Across nearly all sarcoma types, macrophages dominate the immune landscape of STSs. While immune checkpoint inhibitors (ICIs) represent the major immunotherapeutic approach in malignancies with a high load of T cells, the anti-CD47 anti-cancer therapy mostly promotes macrophage-mediated phagocytosis. The efficacy of both therapies is critically dependent on the composition of the tumor microenvironment. Methods: In our study, we evaluated the potential additive effects of combining the anti-PD-1 immunotherapy and anti-CD47 immunotherapy ex vivo. The proportions of tumor cells and tumor-infiltrating lymphocytes were characterized ex vivo from resected tumors of 73 patients who underwent surgery for STS. The expression of CD47 on tumor cells was analyzed by immunohistochemistry. Cell suspensions were obtained from freshly resected tumors and the proportions of CD45 + , CD45 - , CD3 + , CD4 + , and CD8 + cells were measured by flow cytometry. The effect of the anti-PD-1 blockade, anti-CD47 blockade, and the combinatorial application of anti-PD-1 and anti-CD47 therapies on the immune cell activation in vitro was investigated by culturing of cell suspensions at a concentration 0.3x10 6 /ul in the presence/absence of therapeutic monoclonal antibody (Nivolumab 2 ug/ml; anti-CD47 clone MIAP410 20ug/ml) and evaluated by a cytokine Luminex assay (Milliplex® MAP Human Cytokine Bead Panel (Sigma Aldrich) for TNFα, IFNγ, and IL-2 cytokines analysis). Results: The addition of anti-PD1 to CD3/CD28 stimulation drastically increased the production of all cytokines analyzed. This increase in pro-inflammatory cytokine secretion was even more pronounced after adding an anti-CD47 monoclonal antibody to the cell culture. However, a combinatorial application of anti-PD-1 and anti-CD47 agents in vitro was found to limit rather than potentiate the immune activation in the TME of human STS. On an individual level, the most profound response to anti-PD-1 was observed in high-grade leiomyosarcoma and the most profound response to anti-CD47 therapy was observed in an undifferentiated pleiomorphic sarcoma. Conclusions: Our data suggest that combinatorial strategies based on ICIs and anti-CD47 blockade may not provide the desired outcome in STSs. Both therapies, anti-PD-1, and anti-CD47 alone, could however bear a therapeutic potential in selected tumors after close evaluation of the CD47 and PD-1 expression status, as well as the extent of T cell/macrophage infiltration.
Neoadjuvant modified FOLFIRINOX or gemcitabine-nab paclitaxel followed by stereotactic body radiotherapy (SBRT) for patients with locally advanced pancreatic cancer and borderline pancreatic inoperable cancers.
Authors: Ravi Kumar Paluri, Upender Manne, Sushanth Reddy, James Posey, Grant Richard Williams, Olumide B. Gbolahan, Sejong Bae, Rojymon Jacob
Journal: Journal of Clinical Oncology (2022)

e16253 Background: We conducted a single center safety and feasibility trial to investigate feasibility and antitumor activity of sequential FOLFIRINOX or Gemcitabine-nab Paclitaxel (GnP)and Stereotactic Body Radiotherapy (SBRT) in patients with locally advanced pancreatic cancers (LAPC). Methods: Patients with biopsy proven LAPC treated between June 2017 and August 2020 were included. Patients received two months of neo-adjuvant chemotherapy with 4 cycles of FOLFIRINOX or two cycles of GnP followed by SBRT (5 fractions/6.6Gy), total 33gy over 5 days, if no tumor progression after the initial chemotherapy was observed. Patients were reassessed for resectability after SBRT. If unresectable, they were continued on systemic therapy. Primary outcome was safety measured by proportion of grade 3/4 adverse effects. The study is registered with, and is completed. Results: Twenty-five patients enrolled were treated with FOLFIRINOX (n = 16) and GnP (n = 9). Seven (28%) patients did not receive SBRT, due to disease progression (n = 6) after initial systemic therapy, and patients’ preference (n = 1). Eighteen (72%) patients received the SBRT. Thirty-five grade 3 or 4 adverse events were observed with FOLFIRINOX and twenty-five with GnP. No grade 3 or 4 adverse events after SBRT. SBRT was administered within two weeks (median 9 days) after completion of neoadjuvant therapy. Five (27%) patients underwent a resection, all resulting in a complete (R0) resection. The patients who underwent SBRT, the Median overall survival (OS) was 28.39 95%CI (26.45 46.75) and progression free survival was 26.45 95%CI 17.25 46.7. The one-year OS and PFS were 78% (95% CI: 52%-93%) and 67% (95% CI: 41%-87%), respectively. Conclusions: Neoadjuvant FOLFIRINOX or GnP followed by SBRT in patients with LAPC is feasible and shows antitumor activity. There were no safety concerns or treatment delays with incorporation of SBRT. Clinical trial information: NCT03600623.